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Abstract

Background: Development of single ventricle congenital heart disease (SV-CHD) is likely multifactorial, potentially including genetic, environmental, and infectious etiologies. The goal of this study was to evaluate the influence of 5 candidate gene single nucleotide polymorphisms (SNPs) upon single ventricle morphology.

Methods: All patients born with SV-CHD presenting to our institution, including those who have undergone heart transplantation in the past, were approached for enrollment in the study. A blood sample was obtained and DNA was isolated from 145 SV-CHD children (99 male, 46 female). Medical records and echocardiography reports were reviewed to categorize the ventricular morphology at birth as left ventricular (LV, n=58), right ventricular (RV, n=73), or bi-ventricular (Both, n=14). The following candidate SNPs were genotyped with a Taqman 7000 analyzer or by direct sequencing: angiotensinogen M235T (AGT-235), angiotensin II type 2 receptor G1675A, β1 adrenergic receptor C1165G, endogenous nitric oxide synthase G894T, and preproendothelin-1 G5665T. Chi square or Fisher’s exact test were used to test for associations between genotypes and ventricular morphology.

Results: There was a highly significant relationship between the AGT-235 genotype and single ventricle morphology (p<0.0001, Table⇓). Gender and race were analyzed and were not significant confounding variables. The other 4 SNPs demonstrated no significant association with morphology (p>0.4 for each).

Conclusions: The angio-tensinogen M235T polymorphism is associated with single ventricle morphology, with enrichment of the T allele in patients with single left ventricles. Further studies are required to determine if this is a developmental/causal relationship or a secondary enrichment due to a survival benefit in this sub-group of patients.